This invention relates to nonsteroidal compounds, which have a high gestagenic activity.
In addition to a large number of steroid compounds with gestagenic action, gestagens that are not steroids are also known (for example from EP 0 253 500 B1 and WO 94/01412, cf. J. Med. Chem. 38 (1995) 4878).
This invention describes the compounds of general formula I 
in which
R1 and R2 are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group or a halogen atom, and also together with the C-atom of the chain stand for a ring with a total of 3-7 links,
R3 stands for a C1-C5 alkyl group or a partially or completely fluorinated C1-C5 alkyl group,
A stands for a monocyclic or bicyclic aromatic ring that is optionally substituted by one or more radicals, selected from halogen atoms, C1-C5 alkyl groups, C2-C5 alkenyl groups xe2x80x94CR5xe2x95x90CR6R7, whereby R5, R6 and R7 are the same or different and, independently of one another, mean hydrogen atoms or C1-C5 alkyl groups; hydroxy groups, hydroxy groups that carry a C1-C10 acyl group, a C3-C10 carbalkoxyalkyl group, a C2-C5 cyanalkyl group, a C3-C10 unsubstituted or substituted allyl group, a C3-C10 unsubstituted or substituted propargyl group, a C2-C5 alkoxyalkyl group, a C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, the cyano or nitro group, C1-C5 alkoxy groups, C1-C5 alkylthio groups, mono- or disubstituted C1-C10 amino groups or partially or completely fluorinated C1-C5 alkyl groups,
for an ester group xe2x80x94COOR41, whereby R4 means a C1-C5 alkyl group,
for a C2-C5 alkenyl group xe2x80x94CR5xe2x95x90CR6R7, whereby R5, R6 and R7 are the same or different, and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or C1-C5 alkyl groups, for an alkenyl group xe2x80x94Cxe2x95x90CR5, whereby R5 means a hydrogen atom or a C5-C5 alkyl group,
for a partially or completely fluorinated C1-C5 alkyl group,
B stands for a carbonyl group or a CH2 group,
and
Ar stands for a ring system, selected from the group of general partial formulas 2-11, 
xe2x80x83in which
radicals x3a, X4, X6, X7 (in partial formula 2), X4, X6, X7 (in partial formulas 3 and 4), X3a, X3b, X4, X6, X7 (in partial formulas 5, 6 and 7) or Y4, Y5, Y7, Y8 (in partial formulas 8, 9, 10 and 11) are the same or different and are selected from hydrogen atoms, C1-C5 alkyl groups, which in addition can contain a hydroxy group that is optionally etherified with a C1-C5 alkyl group or esterified with a C1-C5 alkanoyl group, partially or completely fluorinated C1-C5 alkyl groups, C2-C5 alkenyl groups
xe2x80x94CR5xe2x95x90CR6R7, whereby R5, R6, and R7 have the above-mentioned meaning, alkenyl groups xe2x80x94Cxe2x95x90CR5, whereby R5 has the above-mentioned meaning,
radicals X3a and X3b also together with the C-atom of benzocondensed ring system 5, 6 or 7 can form a ring with a total of 3-7 links,
and moreover, radicals X4, X6, X7 (in partial formulas 2, 3, 4, 5, 6 and 7) or Y4, Y5, Y7, Y8 (in partial formulas 8, 9, 10 and 11) are selected from halogen atoms, hydroxy groups, C1-C5 alkoxy groups or C1-C5 alkanoyloxy groups,
also if B in general formula I stands for a CH2 group, Ar in addition stands for a phenyl radical of general partial formula 12, 
xe2x80x83in which R9 and R10 are the same or different and mean a cyano group, a nitro group, a halogen atom, a C1-C5 alkyl group, a C1-C5 alkoxy group, a partially or completely fluorinated C1-C5 alkyl group, a C1-C5 alkylthio group, a C1-C5 alkylsulfinyl group or a C1-C5 alkylsulfonyl group, and if B stands for a CH2 group, the physiologically compatible salts of the compounds of general formula I with acids.
The compounds according to the invention are distinguished from the known nonsteroidal compounds with gestagenic action by the substitution pattern on the aryl radical that is on the right in general formula I. In the compounds that are present here, Ar is a benzocondensed, bicyclic ring system, while in the structures that are known from EP 0 253 500 B1 and that can be considered as the closest compounds, a phenyl radical that is substituted in one, two or three places is at this point.
The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the stereoisomers that are detached are part of the subject of this invention.
The substituents that are defined as groups in the compounds of general formula I can have the following meanings in each case.
C1-C5 Alkyl groups can readily be a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl group or an n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A methyl or ethyl group is preferred.
A fluorine, chlorine, bromine or iodine atom can stand for a halogen atom. Here, fluorine, chlorine or bromine is preferred.
If R1 and R2 together with the C-atom of the chain form a 3-7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred.
For a partially or completely fluorinated C1-C5 alkyl group, the perfluorinated alkyl groups that appear above and of the latter mainly the trifluoromethyl group or pentafluoroethyl group as well as partially fluorinated alkyl groups, for example, the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-heptafluoropentyl group are considered.
As a C2-C5 alkenyl group, for example, a vinyl-, allyl- or 2,3-dimethyl-2-propenyl group can appear; if aromatic compound A is substituted with an alkenyl group, preferably it is a vinyl group.
Representatives of a C1-C5 alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, tert-butoxy groups or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy groups. A methoxy or ethoxy group is preferred.
C1-C5 Perfluoroalkoxy groups are the corresponding perfluorinated radicals of the C1-C5 alkoxy groups above.
Monocyclic or bicyclic aromatic ring A, which can be substituted, is a carbocyclic or heterocyclic aryl radical.
In the first case, this is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.
As a heterocyclic radical, for example, a monocyclic heterocyclic radical can be, for example, the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, specifically all possible isomers relative to the positions of the heteroatoms. The thienyl radical is preferred as heteroaryl radical A.
For R4, a methyl, ethyl, n- or iso-propyl group is preferred as a C1-C5 alkyl group in ester group xe2x80x94COOR4.
As a C1-C5 alkyl group for etherification of hydroxy groups, the above-mentioned alkyl groups are suitable; primarily a methyl or ethyl group.
As a C1-C5 alkanoyl group for esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, isobutyl, valeryl or isovaleryl group is suitable, preferably an acetyl group.
If X3a and X3b together with the C-atom of the benzocondensed ring system form a 3-7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred.
As a C1-C5 alkanoyloxy group for X4, X6, X7, Y4, Y5, Y7 or Y8, a formyloxy, acetoxy, propinoyloxy, butyryloxy, iso-butyryloxy, valeryloxy or isovaleryloxy group is suitable, preferably an acetoxy group.
The above-mentioned C1-C5 alkyl groups can stand for C1-C5 alkyl within the C1-C5 alkylthio, C1-C5 alkylsulfinyl or C1-C5 alkylsulfonyl group.
If the compounds of general formula I (B=xe2x80x94CH2) are present as salts, this can be in the form of, for example, hydrochloride, sulfate, nitrate, tartrate or benzoate.
If the compounds according to the invention are present as racemic mixtures, they can be separated into pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated by chromatography into pure isomers on an even optically active carrier material (CHIRALPAK AD(copyright)). It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomeric esters that are obtained by fractionated crystallization or by chromatography, and to saponify the separate esters in each case into the optically pure isomers. For example, mandelic acid, camphorsulfonic acid or tartaric acid can be used as optically active acid.
Preferred according to this invention are those compounds of general formula I, in which:
and the other substituents all have the meanings that are indicated in Formula 1.
In addition, those compounds of general formula I in which Ar stands for a ring system of partial formula 6, 7, 10 or 11 are preferred.
The compounds that are mentioned below are especially preferred according to the invention:
4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,
6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,
5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino)-phthalide,
5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-(hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-hydroxy-4-methyl-4-(4-tolyl)-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylaminol]-phthalide,
5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(3-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-(2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,
5-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide,
5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide,
5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide,
5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide,
6-acetyl-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,
5-[4-(3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
6-(3-hydroxy-3-methyl-1-butinyl)-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,
6-[2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,
6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-4-trifluoromethyl-2,3-benzoxazin-1-one,
4-ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-2,3-benzoxazin-1-one,
4-ethyl-6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,
6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,
4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,
6-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-1-one,
4-ethyl-6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,
6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,
1-(4-nitro-3-trifluoromethylanilino)-4-phenyl-2-trifluoromethyl-2-pentanol,
1-(4-nitro-3-trifluoromethylanilino)-4-phenyl-2-trifluoromethyl-2-pentanol,
5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino)-phthalide,
5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl-propionylamino]-phthalide,
5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl-propionylamino]-phthalide,
5-[2-hydroxy-3-(1-phenyl-cyclohexyl)-2-trifluoromethyl-propionylamino]-phthalide,
2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid,
4-(4-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
4-(4-acetyl-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
4-(4-carbamoylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
4-(4-cyano-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
4-(3-bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,
2-Hydroxy-4-methyl-4-(3-nitro-4-methoxyphenyl)-2-trifluoromethyl-valeric acid,
4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid,
4-(3-chlorophenyl)-4-methyl-2-oxo-valeric acid,
4-(3-bromophenyl)-4-methyl-2-oxo-valeric acid,
4-(2-iodophenyl)-4-methyl-2-oxo-valeric acid,
4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid,
4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid,
4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid,
4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid,
3-(1-phenylcyclopentyl)-pyruvic acid,
6-[3-(1-phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,
6-[3-(1-phenyl-cyclobutyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,
6-[3-(1-phenyl-cyclohexyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,
5-[4-(4-iodo-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,
5-[4-(4-iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,
5-[4-(3-iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,
5-[4-(4-bromo-2-methoxyhenyl)-2-oxo-valeroylamino)-phthalide,
5-[3-(1-phenyl-cyclopentyl)-2-oxo-propionylamino]-phthalide,
6-[4-(5-fluoro-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,
6-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-4-ethyl-2,3-benzoxazin-1-one,
6-(2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,
5-[4(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino)-phthalide,
5-[4-(3-chloro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide.
All above-mentioned compounds are especially preferred in the form of the optical antipodes or the separate diastereomers.
In the gestagen receptor bonding test on the gestagenic action using cytosol from rabbit uterus homogenate and from 3H-progesterone as a reference substance, the new compounds show a strong to very strong affinity to the gestagen receptor (see Table 1).
In addition to their gestagenic action, which is pronounced to different degrees depending on the compound of general formula I that is considered, the new compounds also are distinguished by a more or less strongly pronounced affin-ity to the androgen receptor. The androgen receptor bonding test on androgenic action was carried out using cytosol that consists of rat prostate homogenate and 3H-methyltrienolone as a reference substance.
The new compounds are thus represented relative to the gestagenic compounds from EP 0 253 500 B1 as compounds with a quite novel mix profile, which consists of gestagenic and androgenic action.
For the compounds of general formula I according to the invention, in this case all three of the cases that are pos-sible below are found, which based on the competition factors on progesterone receptor (KFProg) and androgen receptor (KFAndro) are classified within the scope of this invention as follows:
1) Compounds with stronger gestagenic action and less pronounced androgenic action (KFProg less than 1 and KFAndro greater than 5);
2) Compounds with stronger androgenic action and less pronounced gestagenic action (KFAndro less than 5 and KFProg greater than 1);
3) Compounds with pronounced gestagenic and pronounced androgenic action (KFProg less than 1 and KFAndro less than 5).
Depending on their classification according to 1), 2) or 3), the new compounds according to the invention can be used for different medical or pharmaceutical purposes.
In the case of the compounds that are classified under 1) with stronger gestagenic action and less pronounced androgenic action, these are very effective gestagens, which, like the already numerous known gestagenic compounds, are suitable for preserving pregnancies in the case of parenteral administration and in the case of oral administration.
In combination with an estrogen, combination preparations are obtained that can be used for contraception and for the treatment of menopausal symptoms.
Based on their high gestagenic action, the new compounds of general formula I that are classified under 1) can be used, for example, alone or in combination with estrogens in contraceptive preparations. However, all other applications that are known for gestagen are now open to these new compounds (see, e.g., xe2x80x9cKontrazeption mit Hormonen [Contraception with Hormones],xe2x80x9d Hans-Dieter Taubert and Herbet Kuhl, Georg Thieme Verlag Stuttgartxe2x80x94New York, 1995).
Suitable dosages can be determined as a matter of routine, e.g., by determining the bioequivalency, for example in the pregnancy-maintenance test, relative to a known gestagen for a specific use, for example an amount that is bioequivalent to 30 to 150 xcexcg of levonorgestrel for contraception.
The dosage of the compounds according to the invention under 1) in contraceptive preparations is preferably to be 0.01 to 2 mg per day.
The gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations. The daily dose is preferably administered once.
As estrogens, all natural and synthetic compounds that are known as estrogenically active are suitable.
As natural estrogens, these are especially estradiol and also its longer-acting esters, such as valerate, etc. or estriol.
Preferably, however, synthetic estrogens such as ethinyl-estradiol, 14xcex1,17xcex1-ethano-1,3,5(10)-estratriene-3-17xcex2-diol (WO 88/01275), 14xcex1,17xcex1-ethano-1,3,5(10)-estratriene-3,16xcex1,17xcex2-triol (WO 91/08219) or the 15,15-diallyl derivatives of the estradiol, and of these especially 15,16-dimethylestradiol (WO 95/04070) can be mentioned. As a synthetic estrogen, ethinylestradiol is preferred.
Also, the estratrien-3-aminosulfonates that have become known recently (WO 96/05216 and WO 96/05217), derived from estradiol or ethinylestradiol, which are distinguished by low hepatic estrogeneity, are suitable as estrogens for common use with the compounds of general formula I that are classified under 1). Finally, the 14xcex1,15xcex1-methylene steroids from the estrane series, especially the 14xcex1,15xcex1-methylene-17xcex1-estradiol as well as the corresponding 3-aminosulfonate derivatives can be mentioned.
The estrogen is administered in an amount that corresponds to that of 0.01 to 0.05 mg of ethinylestradiol.
The new compounds of general formula I that are classi-fied under 1) can also be used in preparations for treatment of gynecological disorders and for substitution therapy. Because of their advantageous profile of action, these compounds according to the invention are especially well suited for treatment of premenstrual symptoms, such as headaches, depres-sion, water retention and mastodynia. The daily dose in the treatment of premenstrual symptoms is approximately 1 to 20 mg.
Analogously to what is already known for other gestagens, the new compounds can also be used for treating endometrioses.
Finally, these new compounds can also be used as gestagenic components in the compositions for female birth control that have recently become known and that are distinguished by the additional use of a competitive progesterone antagonist (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. by Runnebaum, Rabe and Kieselxe2x80x94Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Groupxe2x80x941991, page 245; WO 93/17686, WO 93/21927, U.S. Pat. No. 5,521,166).
The dosage lies in the range that is already indicated, and the formulation can be carried out as in conventional OC-preparations. The administration of the additional, competitive progesterone antagonist can in this case also be performed sequentially.
Those compounds of the general formula, which are to be categorized as above under 2) and 3), i.e., compounds that have a strong androgenic action (androgenic gestagens), can be used for the production of pharmaceutical preparations for male birth control.
Currently, in several WHO studies, the contraceptive action of a combination that consists of an orally administered gestagen (Depot-medroxy progesterone acetate, levonorgestrel ester, cyproterone acetate) is tested on men with a parenterally administered androgen (testosterone oenanthate).
By contrast, birth control in men is possible with these compounds in one dosage form, specifically an oral dosage form or a dosage form that is to be administered transdermally.
In addition, the compounds according to the invention with androgenic action can be used with older males for male HRT (Hormone Replacement Therapy).
Those compounds of general formula I, which can more likely be classified under 2), i.e., compounds with mainly androgenic action and weaker gestagenic action, can be used for male hormone therapy. Preparations for treating a hyper-gonadism and for treating male infertility and disturbances of potency can be produced with them.
For male birth control and for treating the above-mentioned androgenic disease agents, the compounds according to the invention are used in the dosages that are equivalent in action to the testosterone oenanthate amounts that are used in the WHO studies or to the dosage that is already in androgen therapy of compounds used.
Amounts that are equivalent in action are those amounts that, in the test on androgenic action on the seminal vesicles and/or prostate of the rat (Hershberger Test), achieve comparable action.
For HRT in man, to date a substitution dose of approxi-mately 10 mg/day of testosterone oenanthate is used.
For male birth control studies that are performed by the WHO, different testosterone esters (oenanthate, bucyclate, undecanoate) are used in the range of approximately 10-30 mg/day.
At this point it should be pointed out that the transi-tions between 1), 2) and 3), as regards the correlation according to the invention of various indications with these varying mix profiles 1), 2) and 3), are smooth. The compounds that more likely lie on the edge of the indicated KF areas based on their KFProg and/or KFAndro, can easily be used also for the indications that are assigned to the adjacent mix profile.
The compounds of general formula I also partially show actions on the glucocorticoid and/or mineral corticoid receptor.
The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient, optionally in combination with an estrogen, being processed with the vehicles that are commonly used in galenicals, diluents, optionally taste correctives, etc., and conveyed in the desired form of administration.
For the preferred oral administration, especially tablets, coated tablets, pills, suspension or solutions are suitable.
For parenteral administration, especially oily solutions, such as, for example, solutions in sesame oil, castor oil and cottonseed oil, are suitable. To increase solubility, solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added.
The compounds of general formula I can also be administered continuously by an intrauterine release system (intrauterine system=IUS; e.g., MIRENA(copyright)); the release rate of the active compound(s), is selected in this case in such a way that the dose that is released daily lies within the already indicated dosage range. It is also possible to incorporate the substances according to the invention in a transdermal system and thus to administer them transdermally.
The compounds of general formula I according to the invention can be produced as described below.
1. A carbonyl compound of general formula II 
in which A, B, Ar, R1 and R2 have the meaning that is indicated in formula I, is reacted with a compound of general formula CnF2n+1xe2x80x94SiR3, in which R3 has the meaning that is indicated in general formula 1, in the presence of a catalyst or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to a compound of formula I. As catalysts, fluoride salts or basic compounds such as alkali carbonates are suitable (J. Amer. Chem. Soc. 111, 393 (1989)).
2. A compound of general formula III 
in which A, B, R1, R2 and R3 have the meaning that is indicated in formula 1 and FG means a leaving group, is reacted with a compound Arxe2x80x94NHxe2x80x94R11, whereby R11 means a hydrogen atom or a C1-C5 acyl group, and Ar has the meaning that is indicated in general formula I, whereby optionally then radical R11 is cleaved off to obtain a compound of formula I. In this case, the compound of general formula III optionally can be formed only as an intermediate product, e.g., this can be an acid chloride that is formed as an intermediate product from a corresponding carboxylic acid.
As leaving groups
3. A compound of general formula IV 
in which A, R1, R2 and R3 have the meaning that is indicated in formula I, is reacted with a compound of formula Arxe2x80x94NHxe2x80x94R11, whereby R11 and Ar have the above-indicated meanings, whereby optionally then radical R11 is cleaved off, to obtain a compound of formula I with B in the meaning of a CH2 group.
4. A compound of formula I, which in radical A or in radical Ar contains the grouping aryl-X, whereby xe2x80x9carylxe2x80x9d means an isocyclic or heterocyclic aromatic compound that corresponds to the definitions that are given for formula I and X means a bromine or iodine atom or the group xe2x80x94Oxe2x80x94SO2R12, in which R12 means a C1-C5 perfluoroalkyl group, is reacted under metal catalysis to compound aryl-R13 according to processes that are known in the art with a compound of formula R13xe2x80x94Y, whereby R13 represents an optionally substituted aryl, ethenyl or ethinyl radical and Y represents a hydrogen atom (J. Org. Chem. 43, 2947 (1978)), group B (Oxe2x80x94R14)2 (J. Org. Chem. 58, 2201 (1993)) or Sn(R15)3 (J. Org. Chem. 52, 422 (1987)) with R14 and R15 meaning a phenyl radical or C1-C5 alkyl and R14 also represents hydrogen, Mg-halogen or an alkali metal atom.
5. In a compound of formula I, which contains an alkoxy or acyloxy substituent in A or Ar, the OH group is released, and optionally etherified or esterified in another reaction or, after conversion into a 1-phenyl-5-tetrazolylether, is completely eliminated by hydrogenation (J. Amer. Chem. Soc. 88, 4271 (1966)).
Of all the foregoing process variants, 1. and 2. are suitable for the production of all compounds that fall under general formula I.
Compounds of general formula I can be produced with the third variant, in which B stands for a xe2x80x94CH2 group.
Using the fourth and fifth process variants, functional-izations of already existing compounds of general formula I can be undertaken.
Compounds that were produced according to one of the processes above and in which A is an optionally substituted aromatic ring, optionally can be selectively substituted at this aromatic radical according to known processes. Examples of this process are the catalytic hydrogenation of multiple bonds, nitration and halogenation.
The starting materials that are used in the examples are produced as follows:
4-Methyl-4-phenyl-2-oxovaleric acid
A Grignard solution that is produced from 26.4 g of magnesium and 162 ml of 2-methyl-2-phenyl-1-chloropropane in 150 ml of diethyl ether was added in drops to 600 ml of oxalic acid diethyl ester at xe2x88x9230xc2x0 C. After 2 hours at room temperature, it was added to ammonium chloride solution, extracted with diethyl ether, dried (Na2SO4) and distilled in fractionated form; 84 g of ethyl ester (boiling point 115-120xc2x0 C./0.03 hPa), which is dissolved in 1 l of methanol, is obtained, mixed with 500 ml of 1 m sodium hydroxide and stirred for 1.5 hours at room temperature. After the methanol is evaporated in a vacuum, the residue is dispersed between water and diethyl ether, the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. After concentration by evaporation, 57 g of 4-methyl-4-phenyl-2-oxovaleric acid is obtained as a thick oil.
4,4-Dimethyl-2-oxo-5-hexenoic acid
36 g of 3,3-dimethyl-4-pentenoic acid is obtained as an oil from 50 g of 3,3-dimethyl-4-pentenoic acid methyl ester by saponification with 10% potassium hydroxide. By stirring with thionyl chloride (20 hours, room temperature), the acid chloride is obtained, boiling point 59xc2x0 C./30 hPa. 16 g of it is stirred with 15 g of trimethylsilylcyanide and 0.16 g of zinc iodide for 4 days. After distillation, 13 g of 4,4-dimethyl-2-oxo-5-hexenoic acid nitrile, boiling point 75-85xc2x0 C./30 hPa, is obtained. 2 g of it is saturated with 0.6 ml of methanol in 13 ml of hexane while being cooled with ice with hydrochloric-acid gas, and it is mixed for 2 hours with water. From the hexane phase, after drying (Na2SO4) and concentration by evaporation, 0.558 g of 4,4-dimethyl-2-oxo-5-hexenoic acid methyl ester, boiling point 48xc2x0 C./0.003 hPa, is obtained. 0.535 g of it is saponified with 1.3 ml of 3N sodium hydroxide solution, whereby 0.32 g of 4,4-dimethyl-2-oxo-5-hexenoic acid is obtained as a yellowish liquid.
3-(1-Phenyl-cyclobutyl)-2-oxo-propionic acid
10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at xe2x88x9272 to xe2x88x9269xc2x0 C. After 4 hours at xe2x88x9275xc2x0 C., 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbalde-hyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0xc2x0 C., to a solution, in which previously 5 g of triethyl-2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0xc2x0 C. with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydro-furan/heptane/ethylbenzene. After 20 hours at room tempera-ture, water is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to 90xc2x0 C. with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2SO4) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil.
3-[1-(2-Methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid
Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropyl-amide (2 mol solution) and 46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide are reacted with one another. 5.6 g of 1-(2-methoxy-phenyl)-cyclopropylcarbonitrile, boiling point 104-115xc2x0 C./0.1 mbar, which was also reacted as described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, is obtained. 3-[1-(2-Methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid is thus obtained as an oil.
Analogously to the process that is described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid and for 3-[1-(2-methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid, the acids that are described in Table 2 were obtained.
3-(1-Phenyl-cyclopropyl)-2-oxo-propionic acid
is obtained analogously to the process that is described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid.
3-(1-Phenyl-cyclohexyl)-2-oxo-propionic acid
is obtained analogously to the process that is described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid.
4-(3-Methoxyphenyl)-4-methyl-2-oxo-valeric acid
4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at xe2x88x9270xc2x0 C. with 257 mg of copper bromidedimethylsulfide complex and then stirred at xe2x88x9240xc2x0 C. for 20 minutes. It is cooled again to xe2x88x9270xc2x0 C., and 0.33 ml of 1,3-dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at xe2x88x9270xc2x0 C. and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2SO4) and concentrated by evaporation. After chroma-tography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.
2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid
The Grignard reagent is produced from 1.5 g of magnesium and 10 g of 2-methyl-2-phenylpropyl chloride in 100 ml of diethyl ether, which yields 9.5 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 90xc2x0 C./0.045 hPa, after reaction with 10 g of trifluoro-pyruvic acid ethyl ester.
7.5 g of the ethyl ester is refluxed with 100 ml of potassium hydroxide in methanol (10%) for 18 hours. After concentration by evaporation in a vacuum, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with 2N hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid is obtained as colorless crystals, boiling point 124-126xc2x0 C.
4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0xc2x0 C., and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na2SO4) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester, boiling point 48xc2x0 C./1 hPa, is obtained.
0.8 g of anhydrous aluminum chloride is added to 5 ml of 4-fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, melting point 38-390xc2x0 C., is obtained.
1.9 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10%) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, it is extracted with hexane, and the separated water phase is acidified with 6N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized from hexane. 1.55 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, melting point 102-104xc2x0 C., is obtained.
2-Hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3-thienyl)-2-trifluoromethyl-valeric acid
The mixture of 2-hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3-thienyl)-2-trifluoromethyl-valeric acid (9:1); melting point 150-151xc2x0 C., was produced analogously.
The acids of Table 3 were produced analogously.
By conversion according to the standard process, additional acids are obtained from the acids above or their precursors:
2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid
By heating 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributylvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120xc2x0 C., 2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid ethyl ester, which provides the title compound, melting point 73-74xc2x0 C., by alkaline saponification, is obtained.
4-(4-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
Analogously to the compound above of 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120xc2x0 C. and subsequent acidic hydrolysis of the enol ether and alkaline saponification, melting point 158-162xc2x0 C.
4-(4-Acetyl-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
Analogously to the compound above of 4-(4-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120xc2x0 C., oil.
4-(4-Cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
From 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140xc2x0 C. After saponification, the title acid is obtained as a foam.
4-(4-Carbamoylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
is obtained by treating the ethyl ester of the acid above with hydrogen peroxide and saponification, melting point 244-245xc2x0 C.
4-(4-Cyano-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
From 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140xc2x0 C. After saponification, the title acid is obtained as an amorphous powder.
4-(3-Bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid
From 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid ethyl ester by bromation with N-bromosuccinimide in dimethylformamide at 0xc2x0 C. and subsequent saponification. Melting point 94-96xc2x0 C.
2-Hydroxy-4-methyl-4-(3-nitro-4-methoxyphenyl)-2-trifluoromethyl-valeric acid
This compound is obtained by reaction of 2.5 g of 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid ethyl ester with 4 ml of 100% nitric acid in 12 ml of trifluoroacetic acid for one hour at 0xc2x0 C., melting point 79-80xc2x0 C.
4-(4-Iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid
3.2 g of 4-iodo-2-methoxybenzoic acid-methyl ester in 10 ml of diethyl ether is added to 24.2 mmol of methylmagnesium bromide in 23 ml of diethyl ether. After 20 hours, ammonium chloride solution is added, the ether phase is separated, dried and concentrated by evaporation. 2.4 g of the residue is dissolved in 10 ml of dichloromethane, mixed with 714 mg of 2-trimethylsilyloxy-acrylic acid-ethyl ester, cooled to xe2x88x9270xc2x0 C. and mixed with 0.27 ml of tin(IV) chloride. After 15 minutes, the solution is added to potassium carbonate solution. After extraction with diethyl ether, the organic phase is washed with water, dried and concentrated by evaporation. 500 mg of the 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid ethyl ester that is thus obtained is stirred with 8.6 ml of 1 M sodium hydroxide in ethanol/water (2:1, v/v) for 3 hours at room temperature. After water is added, it is extracted with diethyl ether, the aqueous phase is acidified with 1 m hydrochloric acid and extracted with diethyl ether. After drying and concentration by evaporation, 410 mg of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained as a yellowish oil.
4-(3-Chlorophenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above of an amorphous powder.
4-(3-Bromophenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above of an amorphous powder.
4-(2-Iodophenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above as an amorphous powder.
4-(3-Iodophenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above of an amorphous powder.
4-(4-Iodophenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above as an oil.
4-(5-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above, melting point 58-60xc2x0 C.
4-(4-Bromo-2-methoxyphenyl)-2-oxo-valeric acid
is obtained analogously to the embodiment above as an oil.
3-(1-Phenylcyclopentyl)-pyruvic acid
is obtained analogously to the embodiment above from 1-phenylcyclopentanol with 2-trimethylsilyloxyacrylic acid-ethyl ester and tin(IV) chloride as an oil.
4-Toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester
A Grignard solution, to which 15 ml of oxalic acid diethyl ester is added at xe2x88x9230xc2x0 C. within 30 minutes, is prepared from 2.6 g of magnesium chips and 15 ml of 2-phenyl-1-chloropropane in diethyl ether. It is stirred for one hour at xe2x88x9220xc2x0 C. and for 2 hours at 0xc2x0 C., and then mixed with saturated ammonium chloride solution. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled in a vacuum. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 98-100xc2x0 C./0.03 hpa, is obtained.
4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at xe2x88x9278xc2x0 C. with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at xe2x88x9278xc2x0 C., another 20 ml of 1 M tetrabutylammoinum fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0xc2x0 C., ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100xc2x0 C./0.04 hPa, is obtained.
4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 ml of diethyl ether and stirred at 0xc2x0 C. with 1.3 g of lithium aluminum hydride for one hour at 0xc2x0 C. and for 16 hours at room temperature. A little water is added while being cooled, and it is stirred for one hour. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol, boiling point 120xc2x0 C./0.04 hPa, is obtained.
4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine is mixed at 0xc2x0 C. with 3.8 g of 4-toluenesulfonic acid chloride. After 16 hours at 0xc2x0 C., it is concentrated by evaporation in a vacuum, mixed with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation. By crystallization from ethyl acetate/hexane, 4.9 g of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester, melting point 95-96xc2x0 C., is obtained.
Analogously, 4-toluenesulfonic acid-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentyl)ester, melting point 78xc2x0 C., is obtained.
Analogously, 4-toluenesulfonic acid-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 80-81xc2x0 C., and 4-toluenesulfonic acid-[2-hydroxy-4-(2-methoxy-5-fluorophenyl)-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 93-95xc2x0 C., were produced.
2-(2-Phenylpropyl)-2-trifluoromethyl-oxiran
400 mg of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester in 5 ml of dimethylformamide is mixed at 0xc2x0 C. with 35 mg of sodium hydride (80% in mineral oil). After one hour at 0xc2x0 C., it is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is distilled. 200 mg of 2-(2-phenylpropyl)-2-trifluoromethyl-oxiran, boiling point 110xc2x0 C./1 hPa, is obtained.
4-Bromo-5-aminophthalide
23 g of 3-bromo-4-nitro-1,2-xylene is suspended in 200 ml of pyridine and 600 ml of water and mixed at 60xc2x0 C. in portions with 260 g of potassium permanganate, whereby the temperature rises to 90xc2x0 C. It is heated for 2 more hours to 95xc2x0 C., filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 27 g of 3-bromo-4-nitrophthalic acid is obtained.
12 g of acid is heated for 15 minutes to 220xc2x0 C. and then distilled on a bulb tube. At 0.03 hPa, 10 g of 3-bromo-4-nitrophthalic acid anhydride is distilled.
The anhydride is dissolved in 120 ml of dimethylformamide and is slowly mixed at 0xc2x0 C. with 78.8 ml of a 0.5 M solution of sodium borohydride in dimethylformamide. After 3 hours at 0xc2x0 C., 2N hydrochloric acid is carefully added, and it is extracted with ethyl acetate. After washing with potassium bicarbonate solution, drying (Na2SO4) and concentration by evaporation of the ethyl acetate phase, 6.6 g of 4-bromo-5-nitrophthalide is obtained.
6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33%) that is heated to 60xc2x0 C. and stirred well. After 2 hours at 60xc2x0 C., the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, melting point 176-180xc2x0 C.
6-Bromo-5-aminophthalide
4-Bromo-5-nitrophthalic acid anhydride is produced analogously to the process of 4-bromo-5-nitro-1,2-xylene that is described above.
By boiling with ethanol, a mixture of 2-bromo-6-ethoxycarbonyl-3-nitrobenzoic acid and 3-bromo-2-ethoxy-carbonyl-4-nitrobenzoic acid is obtained from the above.
1.2 ml of oxalyl chloride is carefully added in drops to 7.2 ml of a 0.66 m solution of dimethylformamide in dichloro-methane at 0xc2x0 C. The solution is stirred for 1 hour at 0xc2x0 C. and for 5 minutes at room temperature. After concentration by evaporation in a vacuum, the residue is suspended in 7 ml of acetonitrile, cooled to xe2x88x9235xc2x0 C. and mixed drop by drop with 1.5 g of the ester mixture. After one hour at the same temperature, it is cooled to xe2x88x9270xc2x0 C., and 2.4 ml of a 2 m solution of sodium borohydride in dimethylformamide is added in drops. It is stirred for 20 hours at room temperature, water is added, alkalized with potassium carbonate and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. A mixture of 5-bromo-6-nitrophthalide and 6-bromo-5-nitrophthalide, which is separated on silica gel with hexane/ethyl acetate (95:5), is obtained.
The reduction to aminophthalide is carried out as described above. 6-Bromo-5-aminophthalide, melting point 235-241xc2x0 C., is obtained.
5-Amino-3-(1-propenyl)-phthalide
5 g of 2-bromo-4-nitrobenzoic acid is converted into acid chloride, which is dissolved in 50 ml of tetrahydrofuran and added in drops to 3 ml of allylamine in 20 ml of tetrahydro-furan, by 2 hours of boiling with 30 ml of thionyl chloride and distilling-off of excess thionyl chloride. After 20 hours at room temperature, it is dispersed between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid-allylamide, melting point 98-100xc2x0 C., is obtained.
This material is dissolved in 35 ml of ethanol and added in drops to a mixture of 50 g of iron(II) sulfate, 170 ml of water and 50 ml of ammonia (33%) that is heated to 60xc2x0 C. and stirred well. After 2 hours at 60xc2x0 C., the mixture is absorptively precipitated 5 times with 200 ml of diethyl ether, the diethyl ether phases are concentrated by evaporation, and the residue is crystallized with hexane. 3.1 g of 4-amino-2-bromo-benzoic acid-allylamide, melting point 115-117xc2x0 C., is obtained.
11 g of 4-amino-2-bromobenzoic acid-allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. Then, the solution is diluted with ethyl acetate, washed with 1N hydrochloric acid and then with potassium carbonate solution, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 13.4 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide, melting point 136-138xc2x0 C., is obtained.
3 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide in 100 ml of dimethoxyethane is mixed at xe2x88x9270xc2x0 C. with 14.2 ml of 1.4 M butyllithium in hexane. After 30 minutes at xe2x88x9270xc2x0 C., 1.63 ml of crotonaldehyde is added. The solution is allowed to heat to room temperature, stirred for another 20 hours, 50 ml of 50% acetic acid is added and heated for 6 hours to 60xc2x0 C. Then, it is diluted with water, extracted with ethyl acetate, the ethyl acetate phase is washed with potassium carbonate solution. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane ethyl acetate (98:2), the residue produces 1.1 g of crystalline 5-(2,6-dimethyl-pyrrol-1-yl)-3-(1-propenyl)-phthalide, melting point 91-95xc2x0 C.
1.1 g of 5-(2,5-dimethylpyrrol-1-yl)-3-(1-propenyl)-phthalide, 8.56 g of hydroxylamine-hydrochloride and 4.58 g of potassium hydroxide in 75 ml of ethanol/water (16:6,8, vv) are heated for 24 hours at 120xc2x0 C. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation and chromatographed on silica gel. 640 mg of 5-amino-3-(1-propenyl)-phthalide, melting point 125-130xc2x0 C., is obtained with dichloromethane/methanol (99:1).
The phthalides of Table 4 are obtained analogously.
Analogously to the production of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, the compounds of Tables 5 and 6 are obtained.
4-Bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide
412 mg of 4-methyl-4-phenyl-2-oxovaleric acid is dissolved in 10 ml of dimethylacetamide and mixed under argon at xe2x88x928xc2x0 C. with 261 mg of thionyl chloride. After 20 minutes of stirring at xe2x88x923 to +3xc2x0 C., 228 mg of 4-bromo-5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4) and after the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 mg of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, melting point 150-152xc2x0 C., is obtained.
5-[3-(1-Phenyl-cyclopropyl)-2-oxo-propionylamino]-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopropyl)-2-oxo-propionic acid, melting point 132-138xc2x0 C.
5-[3-(1-Phenyl-cyclobutyl)-2-oxo-propionylamino]-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 142-146xc2x0 C.
5-[3-(1-Phenyl-cyclohexyl)-2-oxo-propionylamino]-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 120-123xc2x0 C.
The compounds of Table 6 were also produced:
6-[3-(1-Phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one
was obtained analogously to the process that is described for 4-bromo-6-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one and 3-(1-phenyl-cyclopropyl)-2-oxo-propionic acid, melting point 197-200xc2x0 C.
6-[3-(1-Phenyl-cyclobutyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one
was obtained analogously to 6-[3-(1-phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one using 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 155-156xc2x0 C.
6-[3-(1-Phenyl-cyclohexyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one
was obtained analogously to 6-[3-(1-phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one using 3-(1-phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 132-134xc2x0 C.
6-(4,4-Dimethyl-2-oxo-5-hexenoylamino)-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4,4-dimethyl-2-oxo-5-hexenoic acid, melting point 103-104xc2x0 C.
6-Bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide
Analogously to the example above, 1.7 g of 6-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide is obtained from 2.0 g of 4-methyl-4-phenyl-2-oxovaleric acid and 1.11 g of 6-bromo-5-aminophthalide with 1.27 g of thionyl chloride in 60 ml of dimethylacetamide, melting point 148-150xc2x0 C.
5-[4-(4-Iodo-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid as a foam.
5-[4-(4-Iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid as an oil.
5-[4-(3-Iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid, melting point 160-161xc2x0 C.
5-[4-(4-Bromo-2-methoxyhenyl)-2-oxo-valeroylamino)-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid, melting point 136-140xc2x0 C.
5-[3-(1-Phenyl-cyclopentyl)-2-oxo-propionylamino]-phthalide
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopentyl)-2-oxo-propionic acid, melting point 140-144xc2x0 C.
6-[4-(5-Fluoro-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-4-methyl-2,3-benzoxazin-1-one
was obtained analogously to the process that is described for 4-bromo-5-94-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4-methyl-2,3-benzoxazin-1-one and 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid, melting point 171-173xc2x0 C.
6-[4-(5-Fluoro-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-4-ethyl-2,3-benzoxazin-1-one
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4-ethyl-2,3-benzoxazin-1-one and 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid, melting point 157-158xc2x0 C.
6-Amino-4-methyl-2,3-benzoxazin-1-one
60 g of 2-methyl-5-nitroacetophenone, 38.5 g of 2,2-dimethyl-1,3-propanediol and 6 g of p-toluenesulfonic acid are boiled in 1 l of toluene with a water separator until water is no longer produced. The solution is washed with potassium bicarbonate, dried (Na2SO4) and concentrated by evaporation. 71.7 g of the crystalline ketal is obtained from pentane.
The latter is oxidized in 1.5 1 of pyridine and 4.5 l of water with 350 g of potassium permanganate, as described above in the production of 4-bromo-5-aminophthalide. 56.4 g of 4-nitro-2-(2,5,5-trimethyl-1,3-dioxan-2-yl)-benzoic acid is obtained.
52 g of the acid is hydrogenated in 500 ml of methanol and 500 ml of ethyl acetate with 10 g of palladium/carbon (10%). 45.5 g of the crystalline amino compound is obtained from pentane.
10 g of the amine is refluxed with 100 ml of concentrated hydrochloric acid for 2 hours. The solvent is concentrated by evaporation in a vacuum, and the residue is refluxed with 15.7 g of hydroxylamine hydrochloride, 8.4 g of potassium hydroxide, 120 ml of ethanol and 50 ml of water for 12 hours. It is diluted with water, and the crystals are suctioned off. After drying, 3.5 g of 6-amino-4-methyl-2,3-benzoxazine-1-one, melting point 291-296xc2x0 C., is obtained.
6-Amino-4-ethyl-2,3-benzoxazin-1-one
is obtained analogously from 2-methyl-5-nitropropiophenone, melting point 89-93xc2x0 C.
6-Amino-1-methyl-1H-benzotriazole
is described in Heterocycles 36, 259 (1993).
5-Amino-benz[1,2,5]oxadiazole
is described in Boll. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36, 37 (1964).
5-Amino-benz[1,2,5]-thiazole
is described in J. Heterocycl. Chem. 11, 777 (1974).
5-Amino-1-indanone.
is described in J. Org. Chem. 27, 70 (1962).
6-Amino-1,2,3,4-tetrahydro-1-naphthalinone
is described in J. Org. Chem. 27, 70 (1962).
6-Amino-3,4-dihydro-1H-2-benzopyran-1-one
is produced by catalytic hydrogenation (palladium/carbon) in ethanol from the corresponding nitro compound (Canad. J. Chem. 61, 2643 (1983).